Surgical ventricular restoration (SVR) or ventriculoplasty of the dilated left ventricle (LV) after antero-apical myocardial infarction (MI) has been proposed as surgical treatment for congestive heart failure (CHF). Patch aneurymorraphy (Dor procedure), infarct exclusion (no patch), Surgical Anterior Ventricular Restoration (SAVER; performed on akinetic infarcts), passive constraint device procedures such as the Acorn CorCapTM Cardiac Support Device (CSD), and cell transplantation are currently being performed. The long-term goal of this research is to use experimental and theoretical models to arrive at an optimal design for SVR of the dilated LV after antero-apical Mi. First, using the finite element (FE) models developed during the previous funding period, designs of Dor, infarct exclusion, SAVER, modified Acorn CSD, and cell transplantation operations will be optimized. FE models will simulate the effect of the location and amount of injected cells in cell transplantation, residual contracting myocytes (dyskinetic vs akinetic infarct), the amount of excluded or resected myocardium, patch stiffness and location (endocardium vs. epicardium) in the Dor/ SAVER operations and the compliance of the Acorn jacket. Next, the ability to enhance BZ systolic function late (3 months) after antero-apical MI will be tested in sheep. Local AAV mediated gene transfer will be used to up-regulate SERCA2a and systemic Doxycyclin will be used to inhibit MMP in the infarct BZ. BZ contractile function will be measured in isolated myocytes and BZ contractile function determined using cardiac MRI with tags based inverse FE calculations. Next, using conductance and micromanometer-tipped catheters, we will test the ability of the Dor procedure or Dor procedure + enhanced BZ systolic function (best therapy identified in Aim 2) in sheep after antero-apical MI to both stabilize LV volume and improve pump function. Finally, the long term (6 month) effect of the Dor procedure + enhanced BZ systolic function (best therapy identified in Aim 3) on LV volume and global LV pump function after transmural antero-apical MI will be measured in sheep. These findings should have a major impact on current surgical practice. PUBLIC HEALTH RELEVANCE: Enlargement of the heart after a myocardial infarction is associated with an increased incidence of congestive heart failure and mortality. However, it remains unclear whether or how the heart should be fixed. In this grant application, we propose to use sophisticated mathematical simulations to determine the optimal design of heart failure operations. In addition, we will use animal experiments to determine whether those heart failure operations produce a stable reduction is heart size. Finally, we will test whether gene and medical therapy, used to supplement the effect of the heart failure operation, allows the heart to squeeze harder and pump better after surgery.